Uric acid activates extracellular signal-regulated kinases and thereafter endothelin-1 expression in rat cardiac fibroblasts.
BACKGROUND
The association between hyperuricemia and cardiovascular diseases has long been recognized. Elevated levels of uric acid may have a causal role in hypertension and cardiovascular diseases. However, the direct effect of uric acid on cardiac cells remains unclear. Therefore, this study was aimed to examine the effect of uric acid in rat cardiac fibroblasts and to identify the putative underlying signaling pathways.


METHODS
Cultured rat cardiac fibroblasts were stimulated with uric acid; cell proliferation and endothelin-1 (ET-1) gene expression were examined. The effect of uric acid on NADPH oxidase activity, reactive oxygen species (ROS) formation, and extracellular signal-regulated kinases (ERK) phosphorylation were tested to elucidate the intracellular mechanism of uric acid in ET-1 gene expression.


RESULTS
Uric acid-increased cell proliferation and ET-1 gene expression. Uric acid also increased NADPH oxidase activity, ROS formation, ERK phosphorylation, and activator protein-1 (AP-1)-mediated reporter activity. Antioxidants suppressed uric acid-induced ET-1 gene expression, and ERK phosphorylation, and AP-1 reporter activities. Mutational analysis of the ET-1 gene promoter showed that AP-1 binding site was an important cis-element in uric acid-induced ET-1 gene expression.


CONCLUSIONS
These results suggest that uric acid-induced ET-1 gene expression, partially by the activation of ERK pathway via ROS generation in cardiac fibroblasts.
Cheng
Tzu-Hurng
TH
Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan, ROC.
Lin
Jia-Wei
JW
Chao
Hung-Hsin
HH
Chen
Yen-Ling
YL
Chen
Cheng-Hsien
CH
Chan
Paul
P
Liu
Ju-Chi
JC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006331:Heart Diseases / Q000378:metabolism*; D033461:Hyperuricemia / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism / Q000494:pharmacology*
D000975:Antioxidants; D019332:Endothelin-1; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014527:Uric Acid; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases